Practice Guideline for the Treatment of Patients With Bipolar Disorder (Revision)

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PART A:
Treatment Recommendations for Patients With Bipolar Disorder

II. FORMULATION AND IMPLEMENTATION OF A TREATMENT PLAN

The following discussion regarding the formulation and implementation of a treatment plan refers specifically to patients with bipolar disorder. Every effort has been made to identify and highlight distinctions between bipolar I and bipolar II disorder in terms of patient response to treatment. However, with few exceptions, data from large trials have been presented in such a way that making such distinctions is difficult. For the treatment of patients with major depressive disorder, readers should refer to the APA Practice Guideline for the Treatment of Patients With Major Depressive Disorder (2).

Initial treatment of bipolar disorder requires a thorough assessment of the patient, with particular attention to the safety of the patient and those around him or her as well as attention to possible comorbid psychiatric or medical illnesses. In addition to the current mood state, the clinician needs to consider the longitudinal history of the patient's illness. Patients frequently seek treatment during an acute episode, which may be characterized by depression, mania, hypomania, or a mixture of depressive and manic features. Treatment is aimed at stabilization of the episode with the goal of achieving remission, defined as a complete return to baseline level of functioning and a virtual lack of symptoms. (Following remission of a depressive episode, patients may remain at particularly high risk of relapse for a period up to 6 months; this phase of treatment, sometimes referred to as continuation treatment [4], is considered in this guideline to be part of maintenance treatment.) After successfully completing the acute phase of treatment, patients enter the maintenance phase. At this point, the primary goal of treatment is to optimize protection against recurrence of depressive, mixed, manic, or hypomanic episodes. Concurrently, attention needs to be devoted to maximizing patient functioning and minimizing subthreshold symptoms and adverse effects of treatment.

Of note, in the treatment recommendations outlined in this guideline, several references are made to adding medications or offering combinations of medications. Patients with bipolar disorder often require such combinations in order to achieve adequate symptom control and prophylaxis against future episodes. However, each additional medication generally increases the side effect burden and the likelihood of drug-drug interactions or other toxicity and therefore must be assessed in terms of the risk-benefit ratio to the individual patient. This guideline has attempted to highlight medication interactions used in common clinical practice that are of particular concern (e.g., interactions between lamotrigine and valproate or between carbamazepine and oral contraceptives). In addition, for several of the medications addressed in this guideline, different preparations or forms are available (e.g., valproic acid and divalproex). Although the guideline refers to these medications in general terms, the form of medication with the best tolerability and fewest drug interactions should be preferred.

At other times in treatment, it may be necessary to discontinue a medication (e.g., because of intolerable side effects) or substitute one medication for another. It is preferable to slowly taper the medication to be discontinued rather than discontinuing it abruptly.

In this revision of the previously published Practice Guideline for the Treatment of Patients With Bipolar Disorder (5), the term "mood stabilizer" has been omitted. Several definitions of what constitutes a mood stabilizer have been proposed and generally include such criteria as proven efficacy for the treatment of mania or depression, absence of exacerbation of manic or mixed symptoms, or prophylactic efficacy. Because of the absence of a consensus definition, this guideline will instead generally refer to specific medications or to the phase of illness in which they may be used.

A. Psychiatric Management

The cross-sectional (i.e., current clinical status) and longitudinal (i.e., frequency, severity, and consequences of past episodes) context of the treatment decision should guide the psychiatrist and bipolar disorder patient in choosing from among various possible treatments and treatment settings. Such treatment decisions must be based on knowledge of the potential beneficial and adverse effects of available options along with information about patient preferences. In addition, treatment decisions should be continually reassessed as new information becomes available, the patient's clinical status changes, or both. Lack of insight or minimization is often a prominent part of bipolar disorder and may at times interfere with the patient's ability to make reasoned treatment decisions, necessitating the involvement of family members or significant others in treatment whenever possible.

At this time, there is no cure for bipolar disorder; however, treatment can significantly decrease the associated morbidity and mortality. The general goals of bipolar disorder treatment are to assess and treat acute exacerbations, prevent recurrences, improve interepisode functioning, and provide assistance, insight, and support to the patient and family. Initially, the psychiatrist will perform a diagnostic evaluation and assess the patient's safety, level of functioning, and clinical needs in order to arrive at a decision about the optimum treatment setting. Subsequently, specific goals of psychiatric management include establishing and maintaining a therapeutic alliance, monitoring the patient's psychiatric status, providing education regarding bipolar disorder, enhancing treatment compliance, promoting regular patterns of activity and of sleep, anticipating stressors, identifying new episodes early, and minimizing functional impairments.

1. Perform a diagnostic evaluation
The evaluation for bipolar disorder requires careful and thorough attention to the clinical history. Patients with bipolar disorder most often exhibit symptoms of depression but may also exhibit substance use, impulsivity, irritability, agitation, insomnia, problems with relationships, or other concerns. Patients rarely volunteer information about manic or hypomanic episodes, so clinicians must probe about time periods with mood dysregulation, lability, or both that are accompanied by associated manic symptoms (e.g., decreased need for sleep, increased energy).

One way to improve efficiency and increase sensitivity in detecting bipolar disorder is to screen for it, particularly in patients with depression, irritability, or impulsivity. The Mood Disorder Questionnaire is a 13-item, self-report screening instrument for bipolar disorder that has been used successfully in psychiatric clinics (6) and in the general population (unpublished 2001 study of R.M.A. Hirschfeld). The general principles and components of a complete psychiatric evaluation have been outlined in the APA Practice Guideline for Psychiatric Evaluation of Adults (7).

2. Evaluate the safety of the patient and others and determine a treatment setting
Suicide completion rates in patients with bipolar I disorder may be as high as 10%-15% (8-13); thus, a careful assessment of the patient's risk for suicide is critical. The overwhelming majority of suicide attempts are associated with depressive episodes or depressive features during mixed episodes. The elements of an evaluation for suicide risk are summarized in . All patients should be asked about suicidal ideation, intention to act on these ideas, and extent of plans or preparation for suicide. Collateral information from family members or others is critical in assessing suicide risk. Access to means of committing suicide (e.g., medications, firearms) and the lethality of these means should also be determined. Other clinical factors that may increase the risk of a patient acting on suicidal ideation should be assessed; these may include substance abuse or other psychiatric comorbidity, such as psychosis. The nature of any prior suicide attempts, including their potential for lethality, should be considered.

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The ability to predict suicide or violence risk from clinical data is somewhat limited. Consequently, patients who exhibit suicidal or violent ideas or intent require close monitoring. Whenever suicidal or violent ideas are expressed or suspected, careful documentation of the decision-making process is essential. Hospitalization is usually indicated for patients who are considered to pose a serious threat of harm to themselves or others. If patients refuse, they can be hospitalized involuntarily if their condition meets criteria of the local jurisdiction for involuntary admission. Severely ill patients who lack adequate social support outside of a hospital setting or demonstrate significantly impaired judgment should also be considered for admission to a hospital. Additionally, those patients who have psychiatric or general medical complications or who have not responded adequately to outpatient treatment may need to be hospitalized. The optimal treatment setting and the patient's ability to benefit from a different level of care should be reevaluated on an ongoing basis throughout the course of treatment.

During the manic phase of bipolar disorder, a calm and highly structured environment is optimal. Such stimuli as television, videos, music, and even animated conversations can heighten manic thought processes and activities. Patients and their families should be advised that during manic episodes, patients may engage in reckless behavior and that, at times, steps should be taken to limit access to cars, credit cards, bank accounts, and telephones or cellular phones.

3. Establish and maintain a therapeutic alliance
Bipolar disorder is a long-term illness that manifests in different ways in different patients and at different points during its course.

Table 1
Characteristics to Evaluate in an Assessment of Suicide Risk in Patients With Bipolar Disorderª

Presence of suicidal or homicidal ideation, intent, or plans
Access to means for suicide and the lethality of those means
Presence of command hallucinations, other psychotic symptoms, or severe anxiety
Presence of alcohol or substance use
History and seriousness of previous attempts
Family history of or recent exposure to suicide

ªAdapted from the APA Practice Guideline for the Treatment of Patients With Major Depressive Disorder (2).

Establishing and maintaining a supportive and therapeutic relationship is critical to the proper understanding and management of an individual patient. A crucial element of this alliance is the knowledge gained about the course of the patient's illness that allows new episodes to be identified as early as possible.

4. Monitor treatment response
The psychiatrist should remain vigilant for changes in psychiatric status. While this is true for all psychiatric disorders, it is especially important in bipolar disorder because limited insight on the part of the patient is so frequent, especially during manic episodes. In addition, small changes in mood or behavior may herald the onset of an episode, with potentially devastating consequences. Such monitoring may be enhanced by knowledge gained over time about particular characteristics of a patient's illness, including typical sequence (e.g., whether episodes of mania are usually followed by episodes of depression) and typical duration and severity of episodes.

5. Provide education to the patient and to the family
Patients with bipolar disorder benefit from education and feedback regarding their illness, prognosis, and treatment. Frequently, their ability to understand and retain this information will vary over time. Patients will also vary in their ability to accept and adapt to the idea that they have an illness that requires long-term treatment. Education should therefore be an ongoing process in which the psychiatrist gradually but persistently introduces facts about the illness. Over an extended period of time, such an approach to patient education will assist in reinforcing the patient's collaborative role in treating this persistent illness. In this capacity, the patient will know when to report subsyndromal symptoms. Printed material on cross-sectional and longitudinal aspects of bipolar illness and its treatment can be helpful, including information available on the Internet (such as that found in the Medical Library at www.medem.com). Similar educational approaches are also important for family members and significant others. They too may have difficulty accepting that the patient has an illness and may minimize the consequences of the illness and the patient's need for continuing treatment (14-17). A list of depressive and bipolar disorder resources, including associations that conduct regular educational meetings and support groups, is provided in Appendix I (p. 37).

6. Enhance treatment compliance
Bipolar disorder is a long-term illness in which adherence to carefully designed treatment plans can improve the patient's health status. However, patients with this disorder are frequently ambivalent about treatment (18). This ambivalence often takes the form of noncompliance with medication and other treatments (19,20), which is a major cause of relapse (21,22).

Ambivalence about treatment stems from many factors, one of which is lack of insight. Patients who do not believe that they have a serious illness are not likely to be willing to adhere to long-term treatment regimens. Patients with bipolar disorder may minimize or deny the reality of a prior episode or their own behavior and its consequences. Lack of insight may be especially pronounced during a manic episode.

Another important factor for some patients is their reluctance to give up the experience of hypomania or mania (19). The increased energy, euphoria, heightened self-esteem, and ability to focus may be very desirable and enjoyable. Patients often recall this aspect of the experience and minimize or deny entirely the subsequent devastating features of full-blown mania or the extended demoralization of a depressive episode. As a result, they are often reluctant to take medications that prevent elevations in mood.

Medication side effects, cost, and other demands of long-term treatment may be burdensome and need to be discussed realistically with the patient and family members. Many side effects can be corrected with careful attention to dosing, scheduling, and preparation. Troublesome side effects that remain must be discussed in the context of an informed assessment of the risks and benefits of the current treatment and its potential alternatives.

7. Promote awareness of stressors and regular patterns of activity and sleep
Patients and families can also benefit from an understanding of the role of psychosocial stressors and other disruptions in precipitating or exacerbating mood episodes. Psychosocial stressors are consistently found to be increased before both manic and depressive episodes (23). Although this relationship was previously thought to hold true only for the first few episodes of bipolar disorder, more recent studies have found that stressors commonly precede episodes in all phases of the illness (24). Social rhythm disruption with disrupted sleep/wake cycles may specifically trigger manic (but not depressive) episodes (25). Of course, some episodes may not be associated with any discernible life events or stressors. Clinically, the pharmacological management of manic or depressive episodes does not depend on whether stressors preceded the episode. However, patients and families should be informed about the potential consequences of sleep disruption on the course of bipolar disorder (26). To target vulnerable times and to generate coping strategies for these stressors, the unique association between specific types of life stressors and precipitating episodes for each patient should also be addressed (27). It is similarly important to recognize distress or dysfunction in the family of a patient with bipolar disorder, since such ongoing stress may exacerbate the patient's illness or interfere with treatment (14,15,28,29).

Patients with bipolar disorder may benefit from regular patterns of daily activities, including sleeping, eating, physical activity, and social and emotional stimulation. The psychiatrist should help the patient determine the degree to which these factors affect mood states and develop methods to monitor and modulate daily activities. Many patients find that if they establish regular patterns of sleeping, other important aspects of life will fall into regular patterns as well.

8. Work with the patient to anticipate and address early signs of relapse
The psychiatrist should help the patient, family members, and significant others recognize early signs and symptoms of manic or depressive episodes. Such identification can help the patient enhance mastery over his or her illness and can help ensure that adequate treatment is instituted as early as possible in the course of an episode. Early markers of episode onset vary from patient to patient but are often usefully predictable across episodes for an individual patient. Many patients experience changes in sleep patterns early in the development of an episode. Other symptoms may be quite subtle and specific to the individual (e.g., participating in religious activities more or less often than usual). The identification of these early prodromal signs or symptoms is acilitated by the presence of a consistent relationship between the psychiatrist and the patient as well as a consistent relationship with the patient's family (27). The use of a graphic display or timeline of life events and mood symptoms can be very helpful in this process (30). First conceived by Kraepelin (31) and Meyer (32) and refined and advanced by Post et al. (30), a life chart provides a valuable display of illness course and episode sequence, polarity, severity, frequency, response to treatment, and relationship (if any) to environmental stressors. A graphic display of sleep patterns may be sufficient for some patients to identify early signs of episodes.

9. Evaluate and manage functional impairments
Episodes of mania or depression often leave patients with emotional, social, family, academic, occupational, and financial problems. During manic episodes, for example, patients may spend money unwisely, damage important relationships, lose jobs, or commit sexual indiscretions. Following mood episodes, they may require assistance in addressing the psychosocial consequences of their actions.

Bipolar disorder is associated with functional impairments even during periods of euthymia, and the presence, type, and severity of dysfunction should be evaluated (33-35). Impairments can include deficits in cognition, interpersonal relationships, work, living conditions, and other medical or health-related needs (36,37). Identified impairments in functioning should be addressed. For example, some patients may require assistance in scheduling absences from work or other responsibilities, whereas others may require encouragement to avoid major life changes while in a depressive or manic state. Patients should also be encouraged to set realistic, attainable goals for themselves in terms of desirable levels of functioning. Occupational therapists may be helpful with addressing functional impairments caused by bipolar disorder.

Patients who have children may need help assessing and addressing their children's needs. In particular, children of individuals with bipolar disorder have genetic as well as psychosocial risk factors for developing a psychiatric disorder; parents may need help in obtaining a psychiatric evaluation for children who show early signs of mood instability.

B. Acute Treatment

1. Manic or mixed episodes
For patients experiencing a manic or mixed episode, the primary goal of treatment is the control of symptoms to allow a return to normal levels of psychosocial functioning. The rapid control of agitation, aggression, and impulsivity is particularly important to ensure the safety of patients and those around them.

Lithium, valproate, and antipsychotic medications have shown efficacy in the treatment of acute mania, although the time to onset of action for lithium may be somewhat slower than that for valproate or antipsychotics. The combination of an antipsychotic with either lithium or valproate may be more effective than any of these agents alone. Thus, the first-line pharmacological treatment for patients with severe mania is the initiation of either lithium plus an antipsychotic or valproate plus an antipsychotic. For less ill patients, monotherapy with lithium, valproate, or an antipsychotic such as olanzapine may be sufficient. Alternatives with less supporting evidence for treatment of manic and mixed states include ziprasidone or quetiapine in lieu of another antipsychotic and carbamazepine or oxcarbazepine in lieu of lithium or valproate. (Although efficacy data for oxcarbazepine remain limited, this medication may have equivalent efficacy and better tolerability than carbamazepine.) Short-term adjunctive treatment with a benzodiazepine may also be helpful. In contrast, antidepressants may precipitate or exacerbate manic or mixed episodes and generally should be tapered and discontinued if possible.

Selection of the initial treatment should be guided by clinical factors such as illness severity, by associated features (e.g., rapid cycling, psychosis), and by patient preference where possible, with particular attention to side effect profiles. A number of factors may lead the clinician to choose one particular agent over another. For example, some evidence suggests a greater efficacy of valproate compared with lithium in the treatment of mixed states. Also, severely ill and agitated patients who are unable to take medications by mouth may require antipsychotic medications that can be administered intramuscularly. Because of the more benign side effect profile of atypical antipsychotics, they are preferred over typical antipsychotics such as haloperidol and chlorpromazine. Of the atypical antipsychotics, there is presently more placebo-controlled evidence in support of olanzapine and risperidone.

If psychosocial therapies are used, they should be combined with pharmacotherapy. Perhaps the only indications for psychotherapy alone for patients experiencing acute manic or mixed episodes are when all established treatments have been refused, involuntary treatment is not appropriate, and the primary goals of therapy are focused and crisis-oriented (e.g., resolving ambivalence about taking medication).

For patients who, despite receiving the aforementioned medications, experience a manic or mixed episode (i.e., a "breakthrough" episode), the first-line intervention should be to optimize the medication dose. Optimization of dosage entails ensuring that the blood level is in the therapeutic range and in some cases achieving a higher serum level (although one still within the therapeutic range). Introduction or resumption of an antipsychotic is often necessary. Severely ill or agitated patients may require short-term adjunctive treatment with an antipsychotic agent or benzodiazepine.

With adequate dosing and serum levels, medications for the treatment of mania generally exert some appreciable clinical effect by the 10th to the 14th day of treatment. When first-line medications at optimal doses fail to control symptoms, recommended treatment options include addition of another first-line medication. Alternative treatment options include adding carbamazepine or oxcarbazepine in lieu of an additional first-line medication, adding an antipsychotic if not already prescribed, or changing from one antipsychotic to another. Of the anti-psychotic agents, clozapine may be particularly effective for treatment of refractory illness. As always, caution should be exercised when combining medications, since side effects may be additive and metabolism of other agents may be affected.

ECT may also be considered for patients with severe or treatment-resistant illness or when preferred by the patient in consultation with the psychiatrist. In addition, ECT is a potential treatment for patients with mixed episodes or for severe mania experienced during pregnancy.

Patients displaying psychotic features during a manic episode usually require treatment with an antipsychotic medication. Atypical antipsychotics are favored because of their more benign side effect profile.

2. Depressive episodes
The primary goal of treatment in bipolar depression, as with nonbipolar depression, is remission of the symptoms of major depression with return to normal levels of psycho-social functioning. An additional focus of treatment is to avoid precipitation of a manic or hypomanic episode.

The first-line pharmacological treatment for bipolar depression is the initiation of either lithium or lamotrigine. The better supported of these is lithium. While standard antidepressants such as SSRIs have shown good efficacy in the treatment of unipolar depression, for bipolar disorder they generally have been studied as add-ons to medications such as lithium or valproate; antidepressant monotherapy is not recommended, given the risk of precipitating a switch into mania. For severely ill patients, some clinicians will initiate treatment with lithium and an antidepressant simultaneously, although there are limited data to support this approach. In patients with life-threatening inanition, suicidality, or psychosis, ECT also represents a reasonable alternative. In addition, ECT is a potential treatment for severe depression during pregnancy. Selection of the initial treatment should be guided by clinical factors such as illness severity, by associated features (e.g., rapid cycling, psychosis), and by patient preference, with particular attention to side effect profiles.

Small studies have suggested that interpersonal therapy and cognitive behavior therapy may also be useful when added to pharmacotherapy during depressive episodes in patients with bipolar disorder. There have been no definitive studies to date of psychotherapy in lieu of antidepressant treatment for bipolar depression. However, a larger body of evidence supports the efficacy of psychotherapy in the treatment of unipolar depression (2).

For patients who, despite receiving maintenance medication treatment, suffer a breakthrough depressive episode, the first-line intervention should be to optimize the dose of the maintenance medication. Optimization of dosage entails ensuring that the serum drug level is in the therapeutic range and in some cases achieving a higher serum level (although one still within the therapeutic range).

For patients who do not respond to optimal maintenance treatment, next steps include adding lamotrigine, bupropion, or paroxetine. Alternative next steps include adding other newer antidepressants (e.g., another SSRI or venlafaxine) or an MAOI. Although there are few empirical data that directly compare risk of switch or efficacy among antidepressants in the treatment of bipolar disorder, tricyclic antidepressants may carry a greater risk of precipitating a switch into hypomania or mania. Also, while MAOIs have generally demonstrated good efficacy, their side effect profile may make other agents preferable as initial interventions (2). ECT should be considered for patients with severe or treatment-resistant depressive episodes or for those episodes with catatonic features.

Patients with psychotic features during a depressive episode usually require adjunctive treatment with an antipsychotic medication. ECT represents a reasonable alternative.

Studies of bipolar depression rarely separate results for patients with bipolar I disorder from those of patients with bipolar II disorder. It is not known whether specific pharmacotherapy regimens differ in efficacy for treatment of bipolar I versus bipolar II depression. However, existing data suggest that for patients with bipolar II disorder, antidepressant treatment-either alone or in combination with a maintenance medication-is less likely to result in a switch into a hypomanic episode relative to those with bipolar I disorder (38).

3. Rapid cycling
The initial intervention for patients who experience rapid-cycling episodes of illness is to identify and treat medical conditions that may contribute to cycling, such as hypothyroidism or drug or alcohol use. Since antidepressants may also contribute to cycling, the need for continued antidepressant treatment should be reassessed; antidepressants should be tapered if possible. The initial treatment for patients who experience rapid-cycling episodes of illness should include lithium or valproate; an alternative treatment is lamotrigine. In many instances, combinations of medications are required (39,40); possibilities include combining two of these agents or combining one of them with an antipsychotic. Because of their more benign side effect profile, atypical antipsychotics are preferred over typical antipsychotics.

C. Maintenance Treatment

Maintenance medication treatment is generally recommended following a single manic episode. Although few studies have been conducted involving patients with bipolar II disorder, consideration of maintenance treatment for this form of the illness is also warranted. Primary goals of treatment include relapse prevention, reduction of subthreshold symptoms, and reduction of suicide risk. Goals also need to include reduction of cycling frequency and mood instability as well as improvement in overall functioning. Pharmacotherapy must be employed in ways that yield good tolerability and do not predispose the patient to nonadherence.

Options with the best empirical evidence to support their use as maintenance treatments include lithium or valproate; possible alternatives include lamotrigine, carbamazepine, or oxcarbazepine. Despite limited data, oxcarbazepine is included-as it was for acute treatment of mania-because its efficacy may be similar to that of carbamazepine but with better tolerability. In general, if one of these medications was used to achieve remission from the most recent depressive or manic episode, it should be continued. Maintenance ECT may also be considered for patients whose acute episode responded to ECT. Selection of the initial treatment should be guided by clinical factors such as illness severity, by associated features (e.g., rapid cycling, psychosis), and by patient preference, with particular attention to side effect profiles.

For patients treated with an antipsychotic medication during the preceding acute episode, the need for ongoing antipsychotic treatment should be reassessed upon entering the maintenance phase. Since antipsychotic agents, particularly typical antipsychotics, may cause tardive dyskinesia with long-term use, antipsychotics should be slowly tapered and discontinued unless they are required to control persistent psychosis or provide prophylaxis against recurrence. While maintenance therapy with atypical antipsychotics may be considered, there is as yet no definitive evidence that their efficacy in maintenance is comparable to that of agents such as lithium or valproate.

Patients with bipolar disorder are likely to gain some additional benefit during the maintenance phase from a concomitant psychosocial intervention that addresses illness management (i.e., adherence, lifestyle changes, and early detection of prodromal symptoms) and interpersonal difficulties. Although not adequately studied to provide evidence-based documentation, supportive and psychodynamic psychotherapy are widely used in addition to medication.

Group psychotherapy, in conjunction with appropriate medication, may also help patients address such issues as adherence to a treatment plan, adaptation to a chronic illness, regulation of self-esteem, and management of marital as well as other psychosocial issues.

Support groups provide useful information about bipolar disorder and its treatment. Patients in these groups often benefit from hearing the experiences of others who are struggling with such issues as denial versus acceptance of the need for medication, problems with side effects, and how to shoulder other burdens associated with the illness and its treatment. Advocacy groups such as the National Depressive and Manic-Depressive Association and the National Alliance for the Mentally Ill (Appendix I) have many local chapters that provide both support and educational material to patients and their families.

Although maintenance medication combinations are often associated with increases in side effects, use of such regimens should be considered for patients who have not responded adequately to simpler regimens. The addition of another maintenance medication, an atypical antipsychotic, or an antidepressant may be necessary for patients who experience either continuing high levels of subthreshold symptoms or a breakthrough episode of illness. There are currently insufficient data to support one combination over another. Maintenance ECT may also be considered for patients whose acute episode responded to ECT.

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